Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

  • ACS Med Chem Lett. 2015 Jul 12;6(8):850-5. doi: 10.1021/acsmedchemlett.5b00226.
Honghe Wan  1 ,  Gretchen M Schroeder  1 ,  Amy C Hart  1 ,  Jennifer Inghrim  1 ,  James Grebinski  1 ,  John S Tokarski  1 ,  Matthew V Lorenzi  1 ,  Dan You  1 ,  Theresa Mcdevitt  1 ,  Becky Penhallow  1 ,  Ragini Vuppugalla  1 ,  Yueping Zhang  1 ,  Xiaomei Gu  1 ,  Ramaswamy Iyer  1 ,  Louis J Lombardo  1 ,  George L Trainor  1 ,  Stefan Ruepp  1 ,  Jonathan Lippy  1 ,  Yuval Blat  1 ,  John S Sack  1 ,  Javed A Khan  1 ,  Kevin Stefanski  1 ,  Bogdan Sleczka  1 ,  Arvind Mathur  1 ,  Jung-Hui Sun  1 ,  Michael K Wong  1 ,  Dauh-Rurng Wu  1 ,  Peng Li  1 ,  Anuradha Gupta  1 ,  P N Arunachalam  1 ,  Bala Pragalathan  1 ,  Sankara Narayanan  1 ,  Nanjundaswamy K C  1 ,  Prakasam Kuppusamy  1 ,  Ashok V Purandare  1
Affiliations
  • 1. Bristol-Myers Squibb R&D , US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States.
PMID: 26288683 DOI: 10.1021/acsmedchemlett.5b00226
Abstract

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of Other Diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

Keywords
BMS-911543; JAK2; myeloproliferative neoplasm; selective inhibitor; structure-guided design.
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